Wyss Institute will lead IARPA-funded brain mapping consortium

IMAGE: See how the Wyss-developed FISSEQ technology is able to capture the location of individual RNA molecules within cells, which will allow the reconstruction of neuronal networks in the 3-dimensional space...
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Credit: Credit: Wyss Institute at Harvard University

(Boston) - The Wyss Institute for Biologically Inspired Engineering at Harvard University today announced a cross-institutional consortium to map the brain's neural circuits with unprecedented fidelity. The consortium is made possible by a $21 million contract from the Intelligence Advanced Research Projects Activity (IARPA) and aims to discover the brain's learning rules and synaptic 'circuit design', further helping to advance neurally-derived machine learning algorithms.

The consortium will leverage the Wyss Institute's FISSEQ (fluorescent in-situ sequencing) method to push forward neuronal connectomics, the science of identifying the neuronal cells that work together to bring about specific brain functions. FISSEQ was developed in 2014 by the Wyss Institute Core Faculty member George Church and colleagues and, unlike traditional sequencing technologies, it provides a method to pinpoint the precise locations of specific RNA molecules in intact tissue. The consortium will harness this FISSEQ capability to accurately trace the complete set of neuronal cells and their connecting processes in intact brain tissue over long distances, which is currently difficult to do with other methods.

Awarded a competitive IARPA MICrONS contract, the consortium will further the overall goals of President Obama's BRAIN initiative, which aims to improve the understanding of the human mind and uncover new ways to treat neuropathological disorders like Alzheimer's disease, schizophrenia, autism and epilepsy. The consortium's work will fundamentally innovate the technological framework used to decipher the principal circuits neurons use to communicate and fulfill specific brain functions. The learnings can be applied to enhance artificial intelligence in different areas of machine learning such as fraud detection, pattern and image recognition, and self-driving car decision making.

"Historically, the mapping of neuronal paths and circuits in the brain has required brain tissue to be sectioned and visualized by electron microscopy. Complete neurons and circuits are then reconstructed by aligning the individual electron microsope images, this process is costly and inaccurate due to use of only one color (grey)," said Church, who is the Principal Investigator for the IARPA MICrONs consortium. "We are taking an entirely new approach to neuronal connectomics--immensely colorful barcodes--that should overcome this obstacle; and by integrating molecular and physiological information we are looking to render a high-definition map of neuronal circuits dedicated first to specific sensations, and in the future to behaviors and cognitive tasks."

Church is Professor of Genetics at Harvard Medical School, and Professor of Health Sciences and Technology at Harvard and MIT.

To map neural connections, the consortium will genetically engineer mice so that each neuron is barcoded throughout its entire structure with a unique RNA sequence, a technique called BOINC (Barcoding of Individual Neuronal Connections) developed by Anthony Zador at Cold Spring Harbor Laboratory. Thus a complete map representing the precise location, shape and connections of all neurons can be generated.

The key to visualizing this complex map will be FISSEQ, which is able to sequence the total complement of barcodes and pinpoint their exact locations using a super-resolution microscope. Importantly, since FISSEQ analysis can be applied to intact brain tissue, the error-prone brain-sectioning procedure that is part of common mapping studies can be avoided and long neuronal processes can be more accurately traced in larger numbers and at a faster pace.

In addition, the scientists will provide the barcoded mice with a sensory stimulus, such as a flash of light, to highlight and glean the circuits corresponding to that stimulus within the much more complex neuronal map. An improved understanding of how neuronal circuits are composed and how they function over longer distances will ultimately allow the team to build new models for machine learning.

The multi-disciplinary consortium spans 6 institutions. In addition to Church, the Wyss Institute's effort will be led by Samuel Inverso, Ph.D., who is a Staff Software Engineer and Co-investigator of the project. Complementing the Wyss team, are co-Principal Investigators Anthony Zador, Ph.D., Alexei Koulakov, Ph.D., and Jay Lee, Ph.D., at Cold Spring Harbor Laboratory. Adam Marblestone, Ph.D., and Liam Paninski, Ph.D. are co-Investigator at MIT and co-Principal Investigator at Columbia University, respectively. The Harvard-led consortium is partnering with another MICrONS team led by Tai Sing Lee, Ph.D. of Carnegie Mellon University as Principal investigator under a separate multi-million contract, with Sandra Kuhlman, Ph.D. of Carnegie Mellon University and Alan Yuille, Ph.D. of Johns Hopkins University as co-Principal investigators, to develop computational models of the neural circuits and a new generation of machine learning algorithms by studying the behaviors of a large population of neurons in behaving animals, as well as the circuitry of the these neurons revealed by the innovative methods developed by the consortium.

"It is very exciting to see how technology developed at the Wyss Institute is now becoming instrumental in showing how specific brain functions are wired into the neuronal architecture. The methodology implemented by this research can change the trajectory of brain mapping world wide," said Wyss Institute Founding director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and the Vascular Biology Program at Boston Children's Hospital and Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.

The Wyss Institute for Biologically Inspired Engineering at Harvard University uses Nature's design principles to develop bioinspired materials and devices that will transform medicine and create a more sustainable world. Wyss researchers are developing innovative new engineering solutions for healthcare, energy, architecture, robotics, and manufacturing that are translated into commercial products and therapies through collaborations with clinical investigators, corporate alliances, and formation of new startups. The Wyss Institute creates transformative technological breakthroughs by engaging in high risk research, and crosses disciplinary and institutional barriers, working as an alliance that includes Harvard's Schools of Medicine, Engineering, Arts & Sciences and Design, and in partnership with Beth Israel Deaconess Medical Center, Brigham and Women's Hospital, Boston Children's Hospital, Dana-Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Boston University, Tufts University, Charité - Universitätsmedizin Berlin, University of Zurich and Massachusetts Institute of Technology.

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